Anti-CD20 monoclonal antibodies (mAbs) are an important component of treatment regimens for B-cell malignancies. Following administration of anti-CD20 mAbs CD20 expression is down-modulated by trogocytosis and internalization. While cells with low or absent CD20 expression can evade further anti-CD20 mAb binding, they are labelled by complement proteins. In particular, complement component C3d is covalently bound to the cell surface. We hypothesized that C3d constitutes a neoantigen that could be targeted by anti-C3d mAbs to enhance anti-CD20 therapy. We derived several hybridomas from mice immunized with human C3d and found to bind three distinct epitopes on C3d. One epitope was shared by all high affinity mAbs, while two other epitopes were bound by low affinity mAbs. From a high affinity murine mAb we derived a human IgG1 chimeric antibody that is highly selective for C3d, does not bind full length C3, and does not cross react with mouse C3d. The chimeric anti-C3d mAb bound immobilized C3d with a Kd of 17nM and cell-bound C3d with a kD of 3.0nM, similar to the kD of 2.4nM of ofatumumab binding to CD20. The anti-C3d antibody mediated complement-dependent cytotoxicity, NK cellular cytotoxicity, and phagocytosis of C3d opsonized cells. Repeat targeting of C3d opsonized cells in the presence of human serum in vitro resulted in increased deposition of C3d leading to a 5-fold increase of binding sites per cell resulting in an auto-amplification loop and the killing of >95% of cells through complement-dependent lysis. We tested activity of the anti-C3d mAb against primary tumor cells from patients with chronic lymphocytic leukemia (CLL) being treated with the anti-CD20 mAb ofatumumab. The first administration of ofatumumab decreased the tumor cell count in the blood of patients by 50% on average. As expected, CLL cells obtained 24 hours after administration of ofatumumab had lost CD20 antigen and carried abundant C3d on their cell surface. Importantly, the anti-C3d chimeric antibody specifically bound CLL cells but no other blood cells, indicating that targeting of C3d preserves the specificity of the initial complement fixing antibody. These studies provide proof of concept that targeting cell deposited C3d can enhance the potency of mAb therapy. Given that our anti-C3d mAb preserves the specificity of the initial mAb, it could augment the potency of many mAbs currently in clinical use by delivering a one-two punch. We conclude that targeting C3d deposited on cancer cells can eliminate antigen escape variants and potentiate existing therapeutic antibodies. Kinase inhibitors such as ibrutinib have advanced treatment of CLL. However, there remains a need for adjunct treatments capable of deepening response or overcoming resistance to kinase inhibitors. CD19/CD3 bispecific antibodies (bsAbs) recruit endogenous T cells to form cytolytic synapses with CD19+ tumor cells. Blinatumomab, a CD19/CD3 bsAb designed in the BiTE format, is FDA approved for the treatment of some forms of acute lymphoblastic leukemia, and has potential for use in other B-cell malignancies. However, due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy. We developed a novel CD19/CD3 bsAb in the single chain-Fv Fc format (19/3-scFv-Fc). With a half-life of approximately 7 days, 19/3-scFv-Fc may be suitable for weekly dosing. To assess the activity of 19/3-scFv-Fc against CLL, we first cultured peripheral blood mononuclear cells (PBMCs) from treatment-nave patients with bsAbs and measured CLL cell killing by flow cytometry. After 12 days, exposure to either 19/3-scFv-Fc or blinatumomab induced >90% killing of CLL cells compared to exposure to the non-targeting bsAb HER2/3-scFv-Fc (P = 0.003, 19/3-scFv-Fc; P = 0.0009, blinatumomab) (n = 12). This anti-leukemic activity was associated with increases in CD8 and CD4 T cell proliferation, activation, and granzyme B expression. In the NOD/SCID/IL2Rnull (NSG) patient-derived xenograft model, once-weekly treatment with 19/3-scFv-Fc eliminated of over 98% of CLL cells in the blood and spleen. In contrast, blinatumomab failed to induce a response, even when given daily for 8 days. Taken together, these data support the investigation of 19/3-scFv-Fc as a promising immunotherapy for CLL.